Heart Failure, Systolic
Conditions
Keywords
nicotinamide riboside, Nicotinamide-Adenine Dinucleotide
Brief summary
Mitochondrial dysfunction has been implicated in heart failure (HF), and is associated with an imbalance in intracellular ratio of reduced nicotinamide-adenine dinucleotide (NADH) to oxidized nicotinamide-adenine dinucleotide (NAD), or the NADH/NAD ratio. In mouse models of HF, we have found that normalization of the NADH/NAD, through supplementation with NAD+ precursors, is associated with improvement in cardiac function. This Study will randomize participants with systolic HF (ejection fraction ≤40%) to treatment with the NAD precursor, nicotinamide riboside (NR) or matching placebo, uptitrated to a final oral dose of 1000mg twice daily, to determine the safety and tolerability of NR in participants with systolic HF.
Detailed description
Aim 1: Determine the safety and tolerability of NR in patients with clinically stable, systolic heart failure (LVEF \<40%). To accomplish this Aim: A) a total of 30 participants with clinically stable, systolic heart failure (LVEF \<40%) will undergo 2:1 randomization to NR 250mg PO twice daily or matching placebo B) NR (or matching placebo), will be increased weekly by 250mg/dose (500mg/day) to a final dose of 1000mg PO twice daily. Clinic visits with labs bi-weekly during dose escalation will assess HF symptoms and monitor labs \[B-type natriuretic peptide (BNP), complete blood count (CBC), glycosylated hemoglobin, alanine aminotransferase (ALT), creatine kinase (CK), insulin/glucose, uric acid, electrolytes, blood urea nitrogen (BUN) and creatinine (Cr). C) to ensure intermediate-term safety and tolerability, participants will continue on their maximum tolerated dose (of NR or placebo) through Study Week 12 Aim 2: Determine whether, at the doses employed, NR and NAD are detectable in whole blood. Aim 3 (Exploratory): Assess the range of potential effect sizes of NR on HF surrogate endpoints using: A) Six-minute walk tests (6MWTs) at each visit (including Screening) to assess functional capacity B) Echocardiography at Baseline and Week 12 to assess LV systolic function (by real-time, 3D echocardiography) and diastolic function (by integrated Doppler and tissue Doppler imaging)
Interventions
DIETARY_SUPPLEMENTnicotinamide riboside
nicotinamide riboside capsule
DRUGPlacebo
matching placebo capsule
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
OTHER
Masking
TRIPLE (Subject, Caregiver, Investigator)
Masking description
Randomization and dispensing of matching placebo will be performed by Investigational Drug Services at the University of Washington
Intervention model description
2:1 randomization to nicotinamide riboside vs. matching placebo
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women aged 18 and older with systolic heart failure \[left ventricular ejection fraction (LVEF) by standard 2D echocardiography or radionuclide ventriculography of ≤40%\] deemed, in the clinical opinion of their treating cardiologist to be non-ischemic or ischemic in origin. * Clinically stable (no cardiac procedures or hospitalizations for hospitalizations for cardiac causes, including HF, ischemia or arrhythmia) within the previous 3 months * Ability to undergo study procedures, including scheduled visits, blood draws and six-minute walk test (6MWT) * Willingness/ability to provide informed consent
Exclusion criteria
* Heart failure with preserved ejection fraction (LVEF greater than 40%) * Heart failure due, in the opinion of their treating cardiologist, to etiologies other than non-ischemic or ischemic. Examples of exclusionary heart failure etiologies include primary valvular disease, or infiltrative or inflammatory cardiomyopathies. * Cardiac surgery, percutaneous coronary intervention (PCI) or cardiac device implantation within the previous 3 months * Hospitalizations for cardiovascular causes, including heart failure, chest pain, stroke, transient ischemic attack or arrhythmias within the previous 3 months * Inability to perform Study visits or procedures (e.g., physical inability to perform 6MWT) * Unwillingness/inability to provide informed consent * ALT greater than 3 times the upper limit of normal, hepatic insufficiency or active liver disease * Recent history of acute gout * Chronic renal insufficiency with creatinine ≥2.5mg/dL * Pregnant (or likely to become pregnant) women * Significant co-morbidity likely to cause death in the 6 month follow-up period * Significant active history of substance abuse within the previous 5 years * Current participation in another long-term clinical trial * History of intolerance to NR precursor compounds, including niacin or nicotinamide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | up to 12 weeks | Adverse Events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| On-Trial Change in Whole Blood NAD+ Levels | Week 12-Week 0 | Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels |
| Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment | 16 weeks | Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment |
| Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) | Week 12 - Week 0 | Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay |
Other
| Measure | Time frame | Description |
|---|---|---|
| Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function | Week 12 - Week 0 | Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography |
| Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function | Week 12 - Week 0 | Tissue Doppler Imaging, e' |
| Exploratory Endpoint: Effect of NR on Functional Capacity | Week 12 - Week 0 | Change in Six Minute Walk Distance |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nicotinamide Riboside Nicotinamide riboside will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12.
nicotinamide riboside: nicotinamide riboside capsule | 20 |
| Placebo Matching placebo will be supplied as 250mg capsules, to be administered orally. The initial dose will be 1 capsule twice daily, followed by weekly up-titration by 1 capsule/dose to a final dose of 4 capsules (1000mg) twice daily at the end of Week 4. Participants will be continued on the final dose up to the final follow up visit (week 12). If, at any step, a dose increase is not tolerated, the maximum previously-tolerated dose will be continued through to week 12.
Placebo: matching placebo capsule | 10 |
| Total | 30 |
Baseline characteristics
| Characteristic | Nicotinamide Riboside | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 58 years | 60 years | 59 years |
| Alanine aminotransferase, U/L | 19.9 U/L | 27.3 U/L | 22.4 U/L |
| Alcohol: Never | 3 Participants | 3 Participants | 6 Participants |
| Aspartate aminotransferase | 19.2 U/L | 24.9 U/L | 21.1 U/L |
| Body temperature | 37 degrees Celsius | 36 degrees Celsius | 37 degrees Celsius |
| Emphysema | 1 Participants | 0 Participants | 1 Participants |
| Estimated glomerular filtration rate | 71 mL/min/1.73_m2 | 67 mL/min/1.73_m2 | 70 mL/min/1.73_m2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 9 Participants | 28 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Heart rate | 67 beats/min | 66 beats/min | 67 beats/min |
| Height | 170 cm | 176 cm | 172 cm |
| Hematocrit | 41 % | 42 % | 41 % |
| Hemoglobin | 13.5 g/dL | 13.8 g/dL | 13.6 g/dL |
| History of atherosclerotic disease (coronary, peripheral or carotid) | 8 Participants | 4 Participants | 12 Participants |
| History of atrial fibrillation | 6 Participants | 7 Participants | 13 Participants |
| History of atrial flutter | 0 Participants | 3 Participants | 3 Participants |
| History of diabetes | 8 Participants | 1 Participants | 9 Participants |
| History of dyslipidemia | 11 Participants | 6 Participants | 17 Participants |
| History of hypertension | 7 Participants | 2 Participants | 9 Participants |
| Insulin resistance (homeostasis model assessment) | 7.0 units | 4.4 units | 6.1 units |
| Left ventricular (LV) ejection fraction [LV stroke volume (SV)/LV end-diastolic volume (LVEDV)] | 28 percentage of ejection fraction | 28 percentage of ejection fraction | 28 percentage of ejection fraction |
| Liver disease | 1 Participants | 0 Participants | 1 Participants |
| Non-ischemic heart failure | 13 Participants | 6 Participants | 19 Participants |
| Platelet count, thousand/uL | 194 cells x 1000/uL | 194 cells x 1000/uL | 194 cells x 1000/uL |
| Previous coronary artery bypass surgery | 2 Participants | 4 Participants | 6 Participants |
| Previous myocardial infarction | 7 Participants | 4 Participants | 11 Participants |
| Previous percutaneous coronary intervention | 4 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 10 Participants | 27 Participants |
| Region of Enrollment United States | 20 participants | 10 participants | 30 participants |
| Serum creatinine | 1.1 mg/dL | 1.2 mg/dL | 1.1 mg/dL |
| Serum glucose | 131.7 mg/dL | 114.1 mg/dL | 125.8 mg/dL |
| Serum potassium | 4.2 mEq/L | 4.3 mEq/L | 4.2 mEq/L |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 15 Participants | 8 Participants | 23 Participants |
| Sitting Blood Pressure Diastolic | 67 mmHg | 64 mmHg | 66 mmHg |
| Sitting Blood Pressure Systolic | 106 mmHg | 106 mmHg | 106 mmHg |
| Smoking: Never | 8 Participants | 4 Participants | 12 Participants |
| Weight | 95 kg | 96 kg | 95 kg |
| White blood count | 6.8 cells x 1000/uL | 6.4 cells x 1000/uL | 6.7 cells x 1000/uL |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 10 |
| other Total, other adverse events | 19 / 20 | 9 / 10 |
| serious Total, serious adverse events | 1 / 20 | 2 / 10 |
Outcome results
Primary
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Adverse Events
Time frame: up to 12 weeks
Population: Total Adverse Events, per participant
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nicotinamide Riboside | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 3.1 events/participant |
| Placebo | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | 3.2 events/participant |
Secondary
Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate)
Mitochondrial Respiration in Isolated Peripheral Blood Mononuclear Cells by the Seahorse (R) Assay
Time frame: Week 12 - Week 0
Population: One study subject randomized to NR withdrew post enrollment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide Riboside | Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) | 21 pmol/min/1,000,000 cells | Standard Error 42 |
| Placebo | Effect of NR on Change in Mitochondrial Function (Maximal Oxygen Consumption Rate) | 2 pmol/min/1,000,000 cells | Standard Error 23 |
p-value: <0.05t-test, 2 sided
Secondary
Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment
Incidence of On-Trial Abnormal Laboratory Values and/or Adverse Events that Are Related to Treatment
Time frame: 16 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nicotinamide Riboside | Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment | 0 participants |
| Placebo | Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment | 0 participants |
p-value: <0.05t-test, 2 sided
Secondary
On-Trial Change in Whole Blood NAD+ Levels
Between-group comparison of On-Trial Change in Whole Blood NAD+ Levels
Time frame: Week 12-Week 0
Population: Post enrollment, one of the study participants randomized to NR withdraw before the study drug was dispensed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide Riboside | On-Trial Change in Whole Blood NAD+ Levels | 29.0 uM | Standard Error 3.2 |
| Placebo | On-Trial Change in Whole Blood NAD+ Levels | -0.3 uM | Standard Error 0.6 |
p-value: <0.0001t-test, 2 sided
Other Pre-specified
Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function
Change in Left Ventricular Ejection Fraction by 3D-Transthoracic Echocardiography
Time frame: Week 12 - Week 0
Population: One study subject randomized to NR withdrew post-enrollment. We were unable to obtain the LVEF for one of the enrolled patient randomized to NR.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide Riboside | Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function | 0.0 percentage of ejection fraction | Standard Error 2.2 |
| Placebo | Exploratory Endpoint: Effect of NR on Change in Left Ventricular Systolic Function | 0.3 percentage of ejection fraction | Standard Error 2.2 |
p-value: <0.05t-test, 2 sided
Other Pre-specified
Exploratory Endpoint: Effect of NR on Functional Capacity
Change in Six Minute Walk Distance
Time frame: Week 12 - Week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide Riboside | Exploratory Endpoint: Effect of NR on Functional Capacity | 6 meters | Standard Error 8 |
| Placebo | Exploratory Endpoint: Effect of NR on Functional Capacity | 1 meters | Standard Error 15 |
p-value: <0.05t-test, 2 sided
Other Pre-specified
Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function
Tissue Doppler Imaging, e'
Time frame: Week 12 - Week 0
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Nicotinamide Riboside | Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function | 0.37 cm/sec | Standard Error 0.54 |
| Placebo | Exploratory Endpoint: Effect of NR on Left Ventricular Diastolic Function | -0.44 cm/sec | Standard Error 0.39 |
p-value: <0.05t-test, 2 sided